COORDINATED EXPRESSION OF PHOSPHOINOSITIDE METABOLIC GENES DURING DEVELOPMENT AND AGING OF HUMAN DORSOLATERAL PREFRONTAL CORTEX. Phosphoinositides, lipid-signaling molecules, participate in diverse brain processes within a wide metabolic cascade. We hypothesized that gene transcriptional networks coordinately regulate the phosphoinositide cascade during human brain Development and Aging. We used the public BrainCloud database for human dorsolateral prefrontal cortex to examine age-related expression levels of 49 phosphoinositide metabolic genes during Development (0 to 20+ years) and Aging (21+ years). We identified three groups of partially overlapping genes in each of the two intervals, with similar intergroup correlations despite marked phenotypic differences between Aging and Development. In each interval, ITPKB, PLCD1, PIK3R3, ISYNA1, IMPA2, INPPL1, PI4KB, and AKT1 are in Group 1, PIK3CB, PTEN, PIK3CA, and IMPA1 in Group 2, and SACM1L, PI3KR4, INPP5A, SYNJ1, and PLCB1 in Group 3. Ten of the genes change expression nonlinearly during Development, suggesting involvement in rapidly changing neuronal, glial and myelination events. Correlated transcription for some gene pairs likely is facilitated by colocalization on the same chromosome band. In conclusion, stable coordinated gene transcriptional networks regulate brain phosphoinositide metabolic pathways during human Development and Aging. COORDINATED EXPRESSION OF PUFA METABOLITE RECEPTOR GENES DURING DEVELOPMENT AND AGING OF HUMAN DORSOLATERAL PREFRONTAL CORTEX. Polyunsaturated fatty acids and their eicosanoid and docosanoid metabolites likely influence behavior by acting on multiple receptors in an interactive way.. Together with Dr. Chuck Chen at the NIAAA, we are examining whether gene transcriptional networks coordinately regulate the coordinated expression of these receptor genes during human brain Development and Aging, using our prior approach to this problem (Rapoport et al. PLoS One 10:e0132675). We use the publicly available BrainCloud database for human dorsolateral prefrontal cortex for this analysis. SCREENING AND RECRUITMENT FOR HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS (HAND) STUDIES AND AN EVALUATION OF HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS IN VIROLOGICALLY CONTROLLED PATIENTS. I am co-investigator on this ongoing NIH protocol (13-N-014). This 8 year multi-institute screening protocol will identify approximately 200 HIV-infected individuals and 100 healthy volunteers for enrollment in multiple HAND studies at the NIH. Subjects undergo a one-time screening and evaluation assessment, which includes neuropsychological testing, brain magnetic resonance imaging (MRI), positron emission tomography (PET) and cerebrospinal fluid (CSF) sampling for virus and inflammatory biomarkers. This observational study will characterize the natural course of HAND in subjects with HIV viral loads < 50 copies/mm3. It should enhance understanding of the CNS as a potential HIV reservoir in virally controlled individuals and help in identifying biomarkers and new therapeutic interventions (see below). This NIH screening protocol also is coordinated with a similar screening protocol on different patient and controls at the USUHS, on which I also am co-investigator. ANAKINRA, A RECOMBINANT HUMAN IL-1 RECEPTOR ANTAGONIST, FOR TREATING NEUROINFLAMMATION IN HIV-1 INFECTION. Based on my suggestion, the multicenter HIV-1 study group at the NIH has written a protocol that recently has been approved by the NIAID and CNS IRBs, to perform a Phase I trial with the interleukin (IL)-1 receptor (IL-1R) antagonist, Anakinra. The protocol is partly funded by a $100,000 Bench to Bedside Award to us. Anakinra is licensed by the FDA, crosses the BBB, has demonstrated safety and efficacy in a number of inflammatory diseases (e.g., rheumatoid arthritis and neonatal onset multisystem inflammatory disorder (NOMID)), and may mitigate neuroinflammation in HAND. We first will conduct a Phase 1 pilot study with Anakinra to address its safety in patients with HAND. The study will be conducted at the NIH Clinical Center and the Johns Hopkins University Department of Neurology. Twelve volunteers with HAND will self-administer daily injections of Anakinra for 8 weeks. Safety will be assessed throughout treatment and afterwards. The study has started. MIGRAINE AS A BIOMARKER OF NEUROINFLAMMATION AND HAND IN HIV-1. On the basis of my review of the literature, I proposed to the HIV-1 research group that migraine headache should be evaluated as a potential biomarker of neuroinflammation in HAND. The prevalence of migraine in HIV-1 patients on antiretroviral therapy (ACT) approximates 50%, compared with 5-15% in the general population, and both migraine and HIV-1 are characterized by neuroinflammation -- increased cytokines and upregulated brain arachidonic acid metabolism. Accordingly, specific migraine questionnaires have been added to the NIH screening protocol.
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